Notch signaling plays well described roles in developmental cell fate decisions, in the regulation of stem cell proliferation and in numerous diseases. However, Notch signaling is also critical for the function of adult neurons. Notch plays a role in memory retention in mice and Drosophila, yet the targets of Notch signaling in neurons are unclear. We have demonstrated that the C. elegans lin-12 Notch receptor acts in adult animals to modulate behavior. In the studies proposed here, we will identify the molecular pathways by which Notch signaling alters neuronal function and behavior using the powerful genetic techniques available in C. elegans. In a pilot screen, we identified five genes expressed in the nervous system that are likely direct targets of Notch. All five genes encode proteins that are likely critical for Notch signaling in vertebrate neurons as well. In this proposal, we address the mechanisms and pathways by which these Notch target genes act in the adult nervous system to regulate neuronal activity and behavior. PUBLIC HEALTH RELEVANCE: Notch signaling is critical for normal function of the human nervous system. Mutations in Notch3 and Jagged1 cause CADASIL and Alagille syndromes, respectively. These are dominantly inherited disorders associated with stroke and dementia. Combined, their incidence is at least 1 in 50,000, although CADASIL is likely under-diagnosed. Recent evidence also suggests that Notch signaling is up-regulated in Down's syndrome patients. Interestingly, Notch and amyloid precursor proteins directly interact suggesting that Notch signaling may be important in the memory defects associated with Alzheimer's disease. There is no effective treatment for these disorders. Given the conservation across species of Notch regulatory mechanisms and targets, we anticipate that identifying the targets of Notch signaling in C. elegans will reveal critical targets of Notch modulation in humans that are relevant in both normal and pathological conditions.